A Gene Signature Identifying CIN3 Regression and Cervical Cancer Survival.

The purpose of this study was to establish a gene signature that may predict CIN3 regression and that may aid in selecting patients who may safely refrain from conization. Oncomine mRNA data including 398 immune-related genes from 21 lesions with confirmed regression and 28 with persistent CIN3 were compared. L1000 mRNA data from a cervical cancer cohort was available for validation (n = 239). Transcriptomic analyses identified TDO2 (p = 0.004), CCL5 (p < 0.001), CCL3 (p = 0.04), CD38 (p = 0.02), and PRF1 (p = 0.005) as upregulated, and LCK downregulated (p = 0.01) in CIN3 regression as compared to persistent CIN3 lesions. From these, a gene signature predicting CIN3 regression with a sensitivity of 91% (AUC = 0.85) was established. Transcriptomic analyses revealed proliferation as significantly linked to persistent CIN3. Within the cancer cohort, high regression signature score associated with immune activation by Gene Set enrichment Analyses (GSEA) and immune cell infiltration by histopathological evaluation (p < 0.001). Low signature score was associated with poor survival (p = 0.007) and large tumors (p = 0.01). In conclusion, the proposed six-gene signature predicts CIN regression and favorable cervical cancer prognosis and points to common drivers in precursors and cervical cancer lesions.

Gain of Chromosomal Region 3q26 as a Prognostic Biomarker for High-Grade Cervical Intraepithelial Neoplasia: Literature Overview and Pilot Study.

Approximately 20-40% of high-grade Cervical Intraepithelial Neoplasia (CIN) regresses spontaneously, but the natural prognosis of an individual lesion is unpredictable. Gain of the chromosomal 3q region, which contains the human telomerase RNA gene on 3q26, is found in CIN lesions and cervical carcinoma and shows correlation with disease grade. The aim of this study is to assess whether 3q26 gain as a single genetic marker can predict the natural prognosis of high-grade CIN, by performing a review of the literature and pilot study. A literature review was conducted. Additionally, we performed a pilot study in 19 patients with histologically confirmed high-grade CIN lesions who were followed for a mean of 115 days, after which loop excision was performed. Fluorescent in situ hybridization analysis was performed on the initial diagnostic biopsies to determine gain of 3q26. Eight studies were included in the literature overview, with a total of 407 patients. Of these, only 22 patients had high-grade lesions. All studies found an association between 3q26 gain and disease prognosis. Positive predictive values (PPV) ranged from 50 to 93%, negative predictive values (NPV) ranged from 75 to 100%. Only five out of 155 patients (3.2%) without 3q26 gain showed disease persistence or progression. In our pilot study on 3q26 gain in high-grade CIN, the PPV of 3q26 gain for disease persistence was 67%, the NPV 100%. All four patients without 3q26 gain showed disease regression. In conclusion, the absence of 3q26 gain in diagnostic biopsies may be applied to identify high-grade CIN lesions with a high probability of disease regression.

Clinical value of fully automated p16/Ki-67 dual staining in the triage of HPV-positive women in the Norwegian Cervical Cancer Screening Program.

BACKGROUND: More accurate biomarkers in cervical cytology screening could reduce the number of women unnecessarily referred for biopsy. This study investigated the ability of p16/Ki-67 dual staining to predict high-grade cervical intraepithelial neoplasia (CIN) in human papillomavirus (HPV)-positive women from the Norwegian Cervical Cancer Screening Program. METHODS: Automated p16/Ki-67 dual staining was performed on liquid-based cytology samples from 266 women who were HPV-positive at their secondary screening. At a mean of 184 days after p16/Ki-67 staining, 201 women had a valid staining result and a conclusive follow-up diagnosis (histological diagnosis or HPV-negative diagnosis with normal cytology findings). The sensitivity and specificity for predicting the follow-up diagnosis were compared for cytology, p16/Ki-67 dual staining, and their combination. RESULTS: Sixty-seven percent of the study sample was p16/Ki-67-positive. The sensitivity of p16/Ki-67 staining for predicting CIN-2/3 was statistically significantly higher than the sensitivity of cytology (0.88 vs 0.79; P = .008), but this was not true for the prediction of CIN-3 (0.94 vs 0.88; P = .23). The specificity of cytology for predicting CIN-3 was significantly higher than the specificity of p16/Ki-67 staining (0.35 vs 0.28; P = .002), but this was not true for CIN-2/3 (0.35 vs 0.31; P = .063). For predicting CIN-2/3 and CIN-3, combination testing gave potentially better sensitivity (0.95 and 0.96, respectively) and better specificity (0.49 and 0.50, respectively). CONCLUSIONS: In a population of HPV-positive women, p16/Ki-67 dual staining was more sensitive but less specific than cytology for predicting high-grade CIN. The advantage of using both tests in different combinations is the potential for increasing the specificity or sensitivity in comparison with both methods performed individually. Cancer Cytopathol 2017;125:283-291. © 2016 American Cancer Society.

Comparison of different commercial methods for HPV detection in follow-up cytology after ASCUS/LSIL, prediction of CIN2-3 in follow up biopsies and spontaneous regression of CIN2-3.

OBJECTIVE: Different Human Papilloma Virus (HPV) tests are currently used. An integrated comparison of the Amplicor, Cobas4800, PreTect HPV-Proofer and APTIMA HPV tests has not been done. METHODS: We compared the high-risk HPV detection power of these HPV tests in 528 consecutive population-based follow-up Liquid-Based Cytology samples (LBC) after ASCUS/LSIL index cytology. Their sensitivity and specificity to detect HPV in LBC, their predictive values of histopathologic CIN2-3 in follow-up punch biopsies and CIN2-3 regression in the subsequent cones was assessed. The HPV subtypes detected by the Linear Array genotyping-test (LA), PreTect HPV-Proofer and Cobas4800 were also compared. The follow-up histopathology was consensus expert-reviewed and Ki67/p16-supported. The predictive values of the HPV results in LBC by the different tests for presence of CIN2-3 in follow-up biopsies, and regression in subsequent cones, was assessed. RESULTS: Amplicor, Cobas4800 and APTIMA show good agreement for HPV-positivity/negativity. PreTect HPV-Proofer has many discrepancies versus any of the other methods. The sensitivities for Amplicor, Cobas4800 and APTIMA to detect CIN2-3 were very high (96-100%), but rather low for PreTect HPV-Proofer (53%). Specificity in case of CIN1 or less in follow-up biopsies of Amplicor and Cobas4800 is lower than APTIMA and highest for PreTect HPV-Proofer. HPV subtyping by LA agreed in 90% with Cobas4800 but 70% with PreTect HPV-Proofer. CONCLUSIONS: The Amplicor, Cobas4800 and APTIMA give comparable results but PreTect HPV-Proofer differs from the other tests, with low sensitivity but higher specificity. None of the methods predicted regression of CIN2-3.

LOH at 1p31 (ARHI) and proliferation in lymph node-negative breast cancer.

BACKGROUND: The mitotic activity index (MAI) is a strong prognosticator in node-negative invasive breast cancer patients. Recently, a correlation between the MAI and specific chromosomal aberrations at chromosome 1p was described. METHODS: Analysis of MAI, immunohistochemical staining patterns for proliferation-associated phosphohistone H3 (PPH3), phosphorylated ERK1/2, p21, cyclin E, Ki67 and cyclin D1 proteins; and prognosis in 158 adjuvant chemotherapy-treated T1-2N0M0 invasive breast cancer patients, analysis of LOH at 1p31 (including ARHI) using the dinucleotide repeats D1S207, D1S430 and D1S464 in 76 patients. Single and multivariate survival analysis was used to evaluate the importance of the various markers tested. RESULTS: LOH at 1p31 did not correlate with MAI nor provide prognostic information. Phosphohistone H3 was the best prognosticator for patients in all age groups with 20 year distant metastasis free survival of distant metastases 93% vs. 72% respectively (p=0.004, HR=4.5). In multivariate analysis, phosphohistone H3<13 vs. > or =13 exceeded the prognostic value of the mitotic activity index. CONCLUSIONS: LOH at 1p31 is common in breast cancer, and correlates with loss of proliferation-associated proteins, but not with MAI, PPH3 or prognosis. PPH3 is the best prognosticator in this study group of adjuvant chemotherapy-treated lymph node-negative breast cancer patients.